Our proposal focuses on two aspects of abnormal immune regulation in MS. 1) Might immune system abnormalities in MS be linked to CNS lesions that arise during the disease? Specifically, might strategically situated lesions induce changes via the autonomic nervous system that result in impaired immune regulation, i.e., loss of suppressor (S) function? Loss of S function would in turn favor disease progression. 2) Can we, by comparing patients with persistently abnormal (progressive MS) or persistently normal (stable MS) S function determine mechanisms whereby abnormal function can be made normal and vice versa? Peripheral blood cells from progressive and stable MS patients and normal controls will be exposed to beta-adrenergic agonists and antagonists, interferons, protein kinase C activators and inhibitors, and T cell mitogens, including anti-CD2 monoclonal antibodies. These agents will be used to study S cell function, T cell activation, and synthesis and phosphorylation of T cell proteins. These agents or their endogenous substrates are likely to be involved in the defects in immune function seen in MS. We will also study CD8+ cells and cell lines from rapidly progressive cases in vitro attempting to restore function by pharmacologic means. Conversely, cells from patients with stable MS (and normal S function) will be subjected to manipulations that may convert their normal function in vitro to abnormal. Mechanisms to be explored with regard to change in suppressor function include (a) are there changes in cell surface marker expression that link with change in function? (b) is there a shift from suppressor to cytotoxic function? (c) are there changes in cell activation mechanisms that correlate with altered S function? Identification of the basis for change in S function would have implications both for understanding abnormalities of immune function in MS and for therapy.